TY - JOUR
T1 - Synthesis of Asparagine Derivatives Harboring a Lewis X Type DC-SIGN Ligand and Evaluation of their Impact on Immunomodulation in Multiple Sclerosis
AU - Doelman, Ward
AU - Marqvorsen, Mikkel H.S.
AU - Chiodo, Fabrizio
AU - Bruijns, Sven C.M.
AU - van der Marel, Gijsbert A.
AU - van Kooyk, Yvette
AU - van Kasteren, Sander I.
AU - Araman, Can
N1 - Funding Information: W.D. was financially supported by a NWO BBoL grant. M.H.S.M. was supported by a Lundbeck Foundation Postdoctoral Abroad grant. F.C. was financially supported by the Amsterdam Infection and Immunity Institute Fellowship and by the NWO Spinoza award of Y.K. C.A. would like to thank NWO for financial support in the form of an ECHO grant. Furthermore, the authors would like to thank A. Kros for granting us access to the JASCO J‐815 CD spectrometer and F. van der Heijden for assistance with compound characterization. Publisher Copyright: © 2020 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/2/5
Y1 - 2021/2/5
N2 - The protein myelin oligodendrocyte glycoprotein (MOG) is a key component of myelin and an autoantigen in the disease multiple sclerosis (MS). Post-translational N-glycosylation of Asn31 of MOG seems to play a key role in modulating the immune response towards myelin. This is mediated by the interaction of Lewis-type glycan structures in the N-glycan of MOG with the DC-SIGN receptor on dendritic cells (DCs). Here, we report the synthesis of an unnatural Lewis X (LeX)-containing Fmoc-SPPS-compatible asparagine building block (SPPS=solid-phase peptide synthesis), as well as asparagine building blocks containing two LeX-derived oligosaccharides: LacNAc and Fucα1-3GlcNAc. These building blocks were used for the glycosylation of the immunodominant portion of MOG (MOG31-55) and analyzed with respect to their ability to bind to DC-SIGN in different biological setups, as well as their ability to inhibit the citrullination-induced aggregation of MOG31-55. Finally, a cytokine secretion assay was carried out on human monocyte-derived DCs, which showed the ability of the neoglycopeptide decorated with a single LeX to alter the balance of pro- and anti-inflammatory cytokines, inducing a tolerogenic response.
AB - The protein myelin oligodendrocyte glycoprotein (MOG) is a key component of myelin and an autoantigen in the disease multiple sclerosis (MS). Post-translational N-glycosylation of Asn31 of MOG seems to play a key role in modulating the immune response towards myelin. This is mediated by the interaction of Lewis-type glycan structures in the N-glycan of MOG with the DC-SIGN receptor on dendritic cells (DCs). Here, we report the synthesis of an unnatural Lewis X (LeX)-containing Fmoc-SPPS-compatible asparagine building block (SPPS=solid-phase peptide synthesis), as well as asparagine building blocks containing two LeX-derived oligosaccharides: LacNAc and Fucα1-3GlcNAc. These building blocks were used for the glycosylation of the immunodominant portion of MOG (MOG31-55) and analyzed with respect to their ability to bind to DC-SIGN in different biological setups, as well as their ability to inhibit the citrullination-induced aggregation of MOG31-55. Finally, a cytokine secretion assay was carried out on human monocyte-derived DCs, which showed the ability of the neoglycopeptide decorated with a single LeX to alter the balance of pro- and anti-inflammatory cytokines, inducing a tolerogenic response.
KW - bioorganic chemistry
KW - glycoconjugates
KW - glycoimmunology
KW - glycopeptides
KW - multiple sclerosis
UR - http://www.scopus.com/inward/record.url?scp=85098216554&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/chem.202004076
DO - https://doi.org/10.1002/chem.202004076
M3 - Article
C2 - 33090600
SN - 0947-6539
VL - 27
SP - 2742
EP - 2752
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
IS - 8
ER -